The overall goal of this research project is to investigate the role of protein phosphatases in long term depression (LTD) of synaptic transmission in the mammalian brain. LTD along with long term potentiation (LTP) are prominent candidates for molecular mechanisms underlying such important neuronal functions as learning and memory formation. In this project, rat hippocampal slices will be used to obtain whole cell recordings of excitatory synaptic responses in CA1 pyramidal cells. The bulk of proposed experiments involve the perfusion of purified protein phosphatases (PP1 and PPP2B) into CA1 pyramidal cells while evoked synaptic responses are monitored. Specifically the following experiments will be performed. (1) Changes in the synaptic strength of cells infused with phosphatases will investigate whether phosphatases are sufficient to induce synaptic depression. (2) Whether the phosphatase-induced synaptic depression shares some of the same mechanisms with LTD will be determined by performing occlusion experiments. (3) Whether infusion of phosphatases modify postsynaptic glutamate receptors will be determined by monitoring the responses to iontophoretically applied AMPA or (4) by monitoring spontaneous EPSCs. (5) The role of increased phosphatase activity in maintaining LTD will be examined by infusing phosphatase inhibitors at various times following the induction of LTD. The results of these experiments will provide important information about the biochemical mechanisms by which synaptic efficacy can be modified and is a prerequisite for a thorough understanding of many important nervous system functions.